M.L.R. Smith

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barretts esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barretts esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barretts esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

Making process, not progress: ASEAN and the evolving East Asian regional order

Since the Asian financial crisis of 1998, regional scholars and diplomats have maintained that the Association of Southeast Asian Nations (ASEAN) represents an evolving economic and security community. In addition, many contend that what is known as the ASEAN process not only has transformed Southeast Asias international relations, but has started to build a shared East Asian regional identity. ASEANs deeper integration into a security, economic, and political community, as well as its extension into the ASEAN Plus Three processes that were begun after the 1997 financial crisis, offers a test case of the dominant assumptions in both ASEAN scholarship and liberal and idealist accounts of international relations theory. Three case studies of ASEAN operating as an economic and security community demonstrate, however, that the norms and practices that ASEAN promotes, rather than creating an integrated community, can only sustain a pattern of limited intergovernmental and bureaucratically rigid interaction.

Constructing communities: the curious case of East Asian regionalism

The prevailing scholarly orthodoxy regarding recent diplomatic initiatives in the Asia-Pacific assumes that East Asia is evolving into a distinctive regional community. The orthodoxy attributes this development to the growing influence of the diplomatic practices espoused by the Association of Southeast Asian States (ASEAN) and its related institutions. However, a paradox remains, namely: despite the failure of ASEANs distinctive practice to fulfil its rhetorical promise in Southeast Asia both immediately prior to and in the aftermath of the Asian financial crisis in 1997, it is nevertheless considered sufficient to validate the projection of ASEAN defined norms onto a wider Pacific canvas. This study analyses how an academic preference for constructivism has misinterpreted the growth in official rhetoric extolling East Asian regionalism since 1997 in a way that has helped produce and reinforce this paradox. By contrast, we contend that government declarations of a developing East Asian identity actually serve to obscure the continuation of traditional interstate relations and do not herald any wider, let alone inexorable, movement towards an integrated regional community.

BayesPeak—an R package for analysing ChIP-seq data

Motivation: Identification of genomic regions of interest in ChIP-seq data, commonly referred to as peak-calling, aims to find the locations of transcription factor binding sites, modified histones or nucleosomes. The BayesPeak algorithm was developed to model the data structure using Bayesian statistical techniques and was shown to be a reliable method, but did not have a full-genome implementation. Results: In this note we present BayesPeak, an R package for genome-wide peak-calling that provides a flexible implementation of the BayesPeak algorithm and is compatible with downstream BioConductor packages. The BayesPeak package introduces a new method for summarizing posterior probability output, along with methods for handling overfitting and support for parallel processing. We briefly compare the package with other common peak-callers. Availability: Available as part of BioConductor version 2.6. URL: http://bioconductor.org/packages/release/bioc/html/BayesPeak.html Contact: jonathan.cairns@cancer.org.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Strategic Terrorism: The Framework and its Fallacies

Abstract This article seeks to lay out a comprehensive framework by which those who utilize a campaign of strategic terrorism seek to attain their ends. It identifies a distinctive modus operandi: 1) disorientation: to alienate the authorities from their citizens, reducing the government to impotence in the eyes of the population; 2) target response: to induce a target to respond in a manner that is favorable to the insurgent cause; 3) gaining legitimacy: to exploit the emotional impact of the violence to insert an alternative political message. By elucidating the strategy of terrorism, the analysis also reveals its inherent limitations. Resting on the premise that a militarily more powerful adversary will in some way feel restrained from bringing the full force of its military superiority to bear, the strategy relies exclusively on the exploitation of the psychological effects of armed action, thereby rendering it vulnerable to those who are willing to view the resolution of clashes of interest principally in terms of the tangibles of military power.

BeadArray expression analysis using bioconductor.

Illumina whole-genome expression BeadArrays are a popular choice in gene profiling studies. Aside from the vendor-provided software tools for analyzing BeadArray expression data (GenomeStudio/BeadStudio), there exists a comprehensive set of open-source analysis tools in the Bioconductor project, many of which have been tailored to exploit the unique properties of this platform. In this article, we explore a number of these software packages and demonstrate how to perform a complete analysis of BeadArray data in various formats. The key steps of importing data, performing quality assessments, preprocessing, and annotation in the common setting of assessing differential expression in designed experiments will be covered.

Whose hearts and whose minds? The curious case of global counter-insurgency

Abstract Traditionally regarded as a secondary activity in military thinking and practice, the notion of counter-insurgency (COIN) has undergone a remarkable renaissance. This analysis traces the origins of this renaissance to two distinctive schools: a neo-classical school and a global insurgency school. The global insurgency school critiques neo-classical thought and presents itself as a more sophisticated appreciation of current security problems. An examination of the evolution of these two schools of counter-insurgency reveals how the interplay between them ultimately leaves us with a confused and contradictory understanding of the phenomenon of insurgency and the policies and strategies necessary to combat it.

illuminaio: An open source IDAT parsing tool for Illumina microarrays

The IDAT file format is used to store BeadArray data from the myriad of genomewide profiling platforms on offer from Illumina Inc. This proprietary format is output directly from the scanner and stores summary intensities for each probe-type on an array in a compact manner. A lack of open source tools to process IDAT files has hampered their uptake by the research community beyond the standard step of using the vendor’s software to extract the data they contain in a human readable text format. To fill this void, we have developed the illuminaio package that parses IDAT files from any BeadArray platform, including the decryption of files from Illumina’s gene expression arrays. illuminaio provides the first open-source package for this task, and will promote wider uptake of the IDAT format as a standard for sharing Illumina BeadArray data in public databases, in the same way that the CEL file serves as the standard for the Affymetrix platform.

The changing security agenda in Southeast Asia: Globalization, new terror, and the delusions of regionalism

The regional economic crisis of 199798 placed a large question mark over the advocacy, much proclaimed between 1990 and 1997, that ASEAN was at the centre of a shift in the global order toward a Pacific Century premised on the Associations practices of multilateral cooperation, dialogue, consensus, and non-interference. Does the aftermath of the crisis, and the new agenda posed by the forces of economic globalization and the seemingly irresolvable low intensity conflicts that bedevil Southeast Asia, require radical re-thinking of the relevance of security arrangements in Pacific Asia that are essentially the product of the Cold War era? This study examines this question by considering the curious external conditions in which ASEAN rose to international prominence, how ASEAN erroneously came to be seen in the 1990s as an apparently new form of security cooperation, and how rising levels of violent internal challenges generated by the forces of globalization threaten Southeast Asias stability. The conclusion is that these forces have exposed ASEANs constituting incoherence as an imitation community and that consequently it is ill equipped to contend with the pressures exerted by the global information age.

The ‘rhinofication’ of South African security

The rhino-poaching crisis in South Africa raises questions about whether it should be tackled through judicial processes or by the application of hard-power methods. The poaching of wildlife has traditionally been met with a harsh response to send a clear message of punitive deterrence. While the reaction of the South African authorities has been no different, the contemporary threat posed by poaching intersects with, and is complicated by, wider concerns such as border security and immigration. In many respects, this has led to what can be termed the �rhinofication� of South African security. South Africa has a long political tradition that relies on force rather than dialogue, negotiation and reform. Yet, the hard-power response to protect the rhino and other large fauna, though necessary at one level, often runs up against the economic frustrations and temptations of a large, predominantly black, under-class, which for generations has been excluded from wildlife management and conservation by white �exceptionalism�. Poachers are thus transformed through their counter-cultural actions into what Eric Hobsbawm termed �social bandits�. While this social chasm lies at the heart of the �rhino wars�, it is clear that in practical terms the lack of a political/poaching settlement in the form of a racially inclusive conservation strategy almost certainly guarantees their continuation.